Diabetes mellitus is a metabolic disorder caused by the inability to produce adequate levels of insulin or effectively use insulin being produced. The result is abnormally high blood glucose levels, which can lead to a number of serious consequences, such as nerve and blood vessel damage, heart disease, kidney disease, stroke, and blindness (6). Obesity associated type II diabetes, in particular, has become increasingly common in our industrial world and accounts for 90% of all diabetes cases (7, 8). Type II diabetes results from pancreatic β-cell impairment and a gradual loss of cellular responsiveness to insulin. While certain genetic factors are linked to an increased risk for type II diabetes, dietary and lifestyle choices have been shown to strongly impact the onset of this disease in all individuals (7, 8). As type II diabetes cases are associated with insulin insensitivity, and because high levels of insulin have been linked to obesity (9), therapeutic interventions that act independently of this hormone are preferred. This can be done through controlling the influx of glucose into the bloodstream from either the liver (e.g. metformin) or from one's diet (e.g. acarbose) (10, 11).
Starch is a prominent source of glucose and calories in many people's diets. The digestion of starch is a multistep process that begins in the oral cavity with the hydrolysis of insoluble starch polymers into shorter oligomers by salivary α-amylase (12). Upon reaching the small intestine, pancreatic α-amylase provides a more extensive hydrolysis, cleaving the starch into a mixture of gluco-oligosaccharides, primarily maltose and maltotriose. The resulting mixture then passes into the brush border of the small intestine where it is processed into glucose by the resident α-glucosidases maltase/glucoamylase and sucrose/isomaltase. The currently used therapeutics were developed primarily as inhibitors of these α-glucosidases rather than α-amylase since in this way it was possible to limit the processing into glucose both of starch and of dietary sugars such as sucrose (13, 14). The α-glucosidase inhibitors currently in medical use, miglitol, voglibose and acarbose, are all small molecule azasugar-based inhibitors, and unfortunately all are associated with deleterious side effects, ranging from diarrhea to hepatotoxicity (15, 16). While this is in part due to the natural consequences of displacement of sugars to the lower gut where anaerobic fermentation can take place, the problems are also due to systemic absorption and a lack of specificity. As a consequence of these side effects these drugs suffer from relatively poor patient compliance, hence there is a need for more targeted therapeutics of this general class.
Human pancreatic α-amylase, which catalyzes the endo-hydrolysis of (1-4)-α-D-glucosidic linkages in starch, represents a good therapeutic target within the starch degradation pathway since it is the enzyme at the top of the starch digestion pyramid (1, 2). It is active within the lumen of the duodenum, thus orally administered inhibitors that stay within the gastro-intestinal tract will be optimally localized for amylase inhibition and will be less likely to cause undesirable side-effects. Specific inhibition of this enzyme over the brush border α-glucosidases limits starch digestion, while allowing oligosaccharides to be processed thereby minimizing the gastrointestinal effects seen with currently used therapeutic inhibitors (3). Achieving such a level of specificity with mechanism-based inhibitors is challenging since these digestive glycosidases use the same mechanism. However, it seemed possible that more specific inhibitors might have evolved in the context of anti-feedant strategies in the natural world. Specific and potent inhibitors of human pancreatic alpha amylase (HPA), the enzyme that hydrolyses the (1-4)-α-D-glucosidic linkages of ingested starch, show promise in the control of blood glucose levels in diabetic and pre-diabetic individuals while minimizing the side effects of more general alpha glucosidase.